1. Field of the Invention
The present invention relates to a composition and method for treatment of chronic inflammatory disorders of the gastrointestinal tract in mammals.
2. Prior Art
Chronic inflammatory disorders of the gastrointestinal tract are generally grouped under the heading of inflammatory bowel disease, although the disease can affect any part of the gastrointestinal tract from the esophagus to the large intestine. Inflammatory bowel disease is of unknown etiology, although psychological, immunologic, and genetic sources have been discussed as possible etiologic factors. The gastrointestinal inflammation associated with inflammatory bowel disease causes a range of symptoms of increasing severity and with a variety of intestinal and extraintestinal manifestations.
The manifestations of chronic inflammatory bowel disease range from mild to very severe, the more severe including colitis, characterized by an inflammatory reaction involving primarily the colonic mucosa, and Crohn's disease, characterized by inflammation throughout the gastrointestinal tract. The clinical features of ulcerative colitis and Crohn's disease can be similar. Characteristic symptoms include abdominal pain, straining, diarrhea with or without blood, fatigue, fever, and weight loss. Even the mildest of these conditions can carry obvious emotional and psychological burdens. The quality of life of an affected individual can be significantly reduced.
Methods of treatment of inflammatory bowel disease generally involve drug therapy directed towards the suppression of gastrointestinal inflammation. Of the anti-inflammatory drugs, adrenal corticosteroids such as prednisone and prednisolone have been found to be the most efficacious treatment of Crohn's disease and ulcerative colitis. However, the effectiveness of corticosteroids in relieving the symptoms of gastrointestinal inflammation is often accompanied by unfortunate steroid side effects, including hair loss, increased water and food intake, weight gain, and immunosuppression. These systemic side effects can develop after even short-term treatment. Thus, a treatment that is effective in controlling the symptoms of gastrointestinal inflammation but with minimal systemic effects has been sought.
Recent investigations have studied the efficacy of budesonide, a corticosteroid analogue with low systemic bioavailability, as a treatment for inflammatory bowel disease. Budesonide has been found to be efficacious when used as an enema to treat colitis. Lofberg et al., Alimentary Pharmacology and Therapeutics, 8(6):623-629 (1994).! The drug has also been used in clinical trials as a treatment for Crohn's disease. Administered in place of a corticosteroid such as prednisone or prednisolone, budesonide minimizes systemic side effects associated with corticosteroid treatment.
A recent clinical trial Rutgeerts et al., The New England Journal of Medicine, 331(13):842-845 (1994)! compared the efficacies and safeties of prednisolone and budesonide in treating Crohn's disease. Granular budesonide was administered in a controlled-release capsule directed for ileal release in a dosage of 9 mg per day for eight weeks and then 6 mg per day for two weeks. The subjects treated with budesonide demonstrated fewer systemic side effects and less adrenal-suppression than those treated with prednisolone. However, budesonide was found to be less efficacious than prednisolone in reducing the symptoms of Crohn's disease.
In another clinical trial investigating the safety and efficacy of budesonide in treating Crohn's disease Greenberg et al., The New England Journal of Medicine 331(13):836-841 (1994)!, groups of subjects received two daily dosages totalling 3, 9, or 15 mg of budesonide per day. The dosage was administered in a formulation of microgranules of budesonide contained in a controlled-ideal-release gelatin capsule. Greenberg et al. found 9 mg to be the lowest effective dose for induction of remission of Crohn's disease. Greenberg et al. additionally found that at such a dose steroid-related side effects, though less severe than those associated with prednisone, were present in a significant proportion of the subjects.
A treatment effective both in treating gastrointestinal inflammation and in reducing the systemic side effects associated with corticosteroid treatment is still being sought.